This invention relates to novel compounds which are potent and highly selective inhibitors of isolated factor Xa or factor Xa when assembled in the prothrombinase complex. These compounds show selectivity for factor Xa versus other proteases of the coagulation (e.g. thrombin, fVIIa, fIXa) or the fibrinolytic cascades (e.g. plasminogen activators, plasmin). In another aspect, the present invention relates to novel monoamidino-containing compounds, their pharmaceutically acceptable salts, and pharmaceutically acceptable compositions thereof which are useful as potent and specific inhibitors of blood coagulation in mammals. In yet another aspect, the invention relates to methods for using these inhibitors as therapeutic agents for disease states in mammals characterized by coagulation disorders.
Hemostasis, the control of bleeding, occurs by surgical means, or by the physiological properties of vasoconstriction and coagulation. This invention is particularly concerned with blood coagulation and ways in which it assists in maintaining the integrity of mammalian circulation after injury, inflammation, disease, congenital defect, dysfunction or other disruption. Although platelets and blood coagulation are both involved in thrombus formation, certain components of the coagulation cascade are primarily responsible for the amplification or acceleration of the processes involved in platelet aggregation and fibrin deposition.
Thrombin is a key enzyme in the coagulation cascade as well as in hemostasis. Thrombin plays a central role in thrombosis through its ability to catalyze the conversion of fibrinogen into fibrin and through its potent platelet activation activity. Direct or indirect inhibition of thrombin activity has been the focus of a variety of recent anticoagulant strategies as reviewed by Claeson, G., xe2x80x9cSynthetic Peptides and Peptidomimetics as Substrates and Inhibitors of Thrombin and Other Proteases in the Blood Coagulation Systemxe2x80x9d, Blood Coag. Fibrinol. 5, 411-436 (1994). Several classes of anticoagulants currently used in the clinic directly or indirectly affect thrombin (i.e. heparins, low-molecular weight heparins, heparin-like compounds and coumarins).
A prothrombinase complex, including Factor Xa (a serine protease, the activated form of its Factor X precursor and a member of the calcium ion binding, gamma carboxyglutamyl (Gla)-containing, vitamin K dependent, blood coagulation glycoprotein family), converts the zymogen prothrombin into the active procoagulant thrombin. Unlike thrombin, which acts on a variety of protein substrates as well as at a specific receptor, factor Xa appears to have a single physiologic substrate, namely prothrombin. Since one molecule of factor Xa may be able to generate up to 138 molecules of thrombin (Elodi et al., Thromb. Res. 15, 617-619 (1979)), direct inhibition of factor Xa as a way of indirectly inhibiting the formation of thrombin may be an efficient anticoagulant strategy. Therefore, it has been suggested that compounds which selectively inhibit factor Xa may be useful as in vitro diagnostic agents, or for therapeutic administration in certain thrombotic disorders, see e.g., WO 94/13693.
Polypeptides derived from hematophagous organisms have been reported which are highly potent and specific inhibitors of factor Xa. U.S. Pat. No. 4,588,587 describes anticoagulant activity in the saliva of the Mexican leech, Haementeria officinalis. A principal component of this saliva was shown to be the polypeptide factor Xa inhibitor, antistasin (ATS), by Nutt, E. et al., xe2x80x9cThe Amino Acid Sequence of Antistasin, a Potent Inhibitor of Factor Xa Reveals a Repeated Internal Structurexe2x80x9d, J. Biol. Chem., 263, 10162-10167 (1988). Another potent and highly specific inhibitor of Factor Xa, called tick anticoagulant peptide (TAP), has been isolated from the whole body extract of the soft tick Omnithidoros moubata, as reported by Waxman, L., et al., xe2x80x9cTick Anticoagulant Peptide (TAP) is a Novel Inhibitor of Blood Coagulation Factor Xaxe2x80x9d Science, 248 593-596 (1990).
Factor Xa inhibitory compounds which are not large polypeptide-type inhibitors have also been reported including: Tidwell, R. R. et al., xe2x80x9cStrategies for Anticoagulation With Synthetic Protease Inhibitors. Xa Inhibitors Versus Thrombin Inhibitorsxe2x80x9d, Thromb. Res., 19, 339-349 (1980); Turner, A. D. et al., xe2x80x9cp-Amidino Esters as Irreversible Inhibitors of Factor IXa and Xa and Thrombinxe2x80x9d, Biochemistry, 25, 4929-4935 (1986); Hitomi, Y. et al., xe2x80x9cInhibitory Effect of New Synthetic Protease Inhibitor (FUT-175) on the Coagulation Systemxe2x80x9d, Haemostasis, 15, 164-168 (1985); Sturzebecher, J. et al., xe2x80x9cSynthetic Inhibitors of Bovine Factor Xa and Thrombin. Comparison of Their Anticoagulant Efficiencyxe2x80x9d, Thromb. Res., 54, 245-252 (1989); Kam, C. M. et al., xe2x80x9cMechanism Based Isocoumarin Inhibitors for Trypsin and Blood Coagulation Serine Proteases: New Anticoagulantsxe2x80x9d, Biochemistry, 27, 2547-2557 (1988); Hauptmann, J. et al., xe2x80x9cComparison of the Anticoagulant and Antithrombotic Effects of Synthetic Thrombin and Factor Xa Inhibitorsxe2x80x9d, Thromb. Haemost., 63, 220-223 (1990); and the like.
Others have reported Factor Xa inhibitors which are small molecule organic compounds, such as nitrogen containing heterocyclic compounds which have amidino substituent groups, wherein two functional groups of the compounds can bind to Factor Xa at two of its active sites. For example, WO 98/28269 describes pyrazole compounds having a terminal C(xe2x95x90NH)xe2x80x94NH2 group; WO 97/21437 describes benzimidazole compounds substituted by a basic radical which are connected to a naththyl group via a straight or branched chain alkylene, xe2x80x94C(xe2x95x90O) or xe2x80x94S(xe2x95x90O)2 bridging group; WO 99/10316 describes compounds having a 4-phenyl-N-alkylamidino-piperidine and 4-phenoxy-N-alkylarnidino-piperidine group connected to a 3-amidinophenyl group via a carboxamidealkyleneamino bridge; and EP 798295 describes compounds having a 4-phenoxy-N-alkylamidino-piperidine group connected to an amidinonaphthyl group via a substituted or unsubstituted sulfonamide or carboxamide bridging group.
There exists a need for effective therapeutic agents for the regulation of hemostasis, and for the prevention and treatment of thrombus formation and other pathological processes in the vasculature induced by thrombin such as restenosis and inflammation. In particular, there continues to be a need for compounds which selectively inhibit factor Xa or its precursors. Compounds that have different combinations of bridging groups and functional groups than compounds previously discovered are needed, particularly compounds which selectively or preferentially bind to Factor Xa. Compounds with a higher degree of binding to Factor Xa than to thrombin are desired, especially those compounds having good bioavailability and/or solubility.
The present invention relates to novel compounds which inhibit factor Xa, their pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, and pharmaceutically acceptable compositions thereof which have particular biological properties and are useful as potent and specific inhibitors of blood coagulation in mammals. Pharmaceutical compositions of the invention may be used to prevent or treat a condition in a mammal characterized by undesired thrombosis. In another aspect, the invention relates to methods of using these inhibitors as diagnostic reagents or as therapeutic agents for disease states in mammals which have coagulation disorders, such as in the treatment or prevention of a condition in a mammal characterized by undesired thrombosis such as, for example, any thrombotically mediated acute coronary or cerebrovascular syndrome, any thrombotic syndrome occurring in the venous system, any coagulopathy, and any thrombotic complications associated with extracorporeal circulation or instrumentation, and for the inhibition of coagulation of biological samples and blood in biological samples.
In certain embodiments, this invention relates to novel compounds which are potent and highly selective inhibitors of isolated factor Xa or factor Xa when assembled in the prothrombinase complex. These compounds show selectivity for factor Xa versus other proteases of the coagulation cascade (e.g. thrombin, etc.) or the fibrinolytic cascade, and are useful as diagnostic reagents as well as antithrombotic agents.
In a preferred embodiment, the present invention provides a compound of the formula I: 
wherein:
A is selected from:
(a) C1-C6-alkyl;
(b) C3-C8-cycloalkyl;
(c) xe2x80x94N(xe2x80x94R2,xe2x80x94R3), R3xe2x80x94C(xe2x95x90Nxe2x80x94R2)xe2x80x94, (xe2x80x94R2, xe2x80x94R3)Nxe2x80x94C(xe2x95x90Nxe2x80x94R2)xe2x80x94, (xe2x80x94R2, xe2x80x94R3)Nxe2x80x94C(xe2x95x90Nxe2x80x94R2)xe2x80x94N(xe2x80x94Rxe2x80x94)xe2x80x94
(d) phenyl, which is independently substituted with 0-2 R1 substituents;
(e) naphthyl, which is independently substituted with 0-2 R1 substituents; and
(f) a monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are selected from N, O and S, and wherein the ring system may be substituted with 0-2 R1 substituents;
R1 is selected from:
Halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8scycloalkyl, C0-4alkylC3-8cycloalkyl, xe2x80x94CN, xe2x80x94NO2, R2xe2x80x94C(xe2x95x90Nxe2x80x94R3)xe2x80x94, (xe2x80x94R2, xe2x80x94R3)Nxe2x80x94C(xe2x95x90Nxe2x80x94R2)xe2x80x94, (xe2x80x94CH2)mNR2R3, xe2x80x94C(xe2x95x90O)xe2x80x94N(xe2x80x94R2, xe2x80x94R3), xe2x80x94SO2N(xe2x80x94R2, xe2x80x94R3), xe2x80x94SO2R2, xe2x80x94CF3, xe2x80x94OR2, and a 5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogen atoms on the aromatic heterocyclic system may be independently replaced with a member selected from the group consisting of halo, C1-C4-alkyl, xe2x80x94CN C1-4alkyl, C2-6alkenyl, C2-6alkenyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl and xe2x80x94NO2;
R2 and R3 are independently selected from the group consisting of:
H, xe2x80x94OR2, xe2x80x94N(xe2x80x94R2, xe2x80x94R3), xe2x80x94C1-4alkyl, xe2x80x94C2-6alkenyl, xe2x80x94C2-6alkynyl, xe2x80x94C3-8cycloalkyl, xe2x80x94C0-4alkylC3-8cycloalkyl, xe2x80x94C0-4alkylphenyl and xe2x80x94C0-4alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, xe2x80x94C1-4alkyl, xe2x80x94C2-6alkenyl, xe2x80x94C2-6alkynyl, xe2x80x94C3-8cycloalkyl, xe2x80x94C0-4alkylC3-8cycloalkyl, xe2x80x94CN, and xe2x80x94NO2;
or R2 and R3 taken together can form a 3-8 membered cycloalkyl or a heterocyclic ring system, wherein the heterocyclic ring system may have from 5 to 10 ring atoms, with 1 to 2 rings being in the ring system and contain from 1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogen atoms on the heterocyclic ring system may be independently replaced with a member selected from the group consisting of halo, C1-C4-alkyl, xe2x80x94CN xe2x80x94C1-4alkyl, xe2x80x94C2-6alkenyl, xe2x80x94C2-6alkynyl, xe2x80x94C3-8cycloalkyl, xe2x80x94C0-4alkylC3-8cycloalkyl and xe2x80x94NO2;
m is an integer of 0-2;
Q is a member selected from the group consisting of:
a direct link, xe2x80x94CH2xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94N(R4)xe2x80x94, xe2x80x94N(R4)CH2xe2x80x94, xe2x80x94Cxe2x95x90N(R4)xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94N(R4)xe2x80x94, xe2x80x94N(R4)xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94SO2xe2x80x94N(R4)xe2x80x94 and xe2x80x94N(R4)xe2x80x94SO2xe2x80x94;
R4 is selected from:
H, xe2x80x94C1-4alkyl, xe2x80x94C2-6alkenyl, xe2x80x94C2-6alkynyl, xe2x80x94C3-8cycloalkyl, xe2x80x94C0-4alkylC3-8cycloalkyl, xe2x80x94C0-4alkylphenyl and xe2x80x94C0-4alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, xe2x80x94C1-4alkyl, xe2x80x94C2-6alkenyl, xe2x80x94C2-6alkynyl, xe2x80x94C3-8cycloalkyl, xe2x80x94C0-4alkylC3-8cycloalkyl, xe2x80x94CN, and xe2x80x94NO2;
D is a member selected from the group consisting of:
(a) phenyl, which is independently substituted with 0-2 R1a substituents; and
(b) an aromatic six-membered heterocyclic ring having from 1-2 ring nitrogen atoms, and wherein the ring atoms may be substituted with 0-2 R1a substituents;
R1a is selected from:
Halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, xe2x80x94CN, xe2x80x94NO2, (CH2)mNR2aR3a, SO2NR2aR3a, SO2R2a, CF3, OR2a, and a 5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogen atoms on the aromatic heterocyclic system may be independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, xe2x80x94CN and xe2x80x94NO2;
R2a and R3a are independently selected from the group consisting of:
C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, C0-4alkylphenyl and C0-4alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, xe2x80x94CN and xe2x80x94NO2;
M is a member selected from the group consisting of:
xe2x80x94N(R16)xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94N(R16)xe2x80x94C(xe2x95x90S)xe2x80x94, xe2x80x94C(xe2x80x94R17,xe2x80x94R18)xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x80x94R17,xe2x80x94R18)xe2x80x94C(xe2x95x90S)xe2x80x94, xe2x80x94C(xe2x80x94R17,R17a)xe2x80x94C(xe2x80x94R18,xe2x80x94R18a)xe2x80x94, xe2x80x94C(xe2x80x94R19,xe2x80x94R19a)xe2x80x94C(xe2x80x94R17,xe2x80x94R17a)xe2x80x94C(xe2x80x94R18,xe2x80x94R18a)xe2x80x94, xe2x80x94C(xe2x80x94R17)xe2x95x90C(xe2x80x94R18)xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x80x94R17)xe2x95x90C(xe2x80x94R18)xe2x80x94C(xe2x95x90S)xe2x80x94, xe2x80x94C(xe2x80x94R17)xe2x95x90C(xe2x80x94R18)xe2x80x94, xe2x80x94Oxe2x80x94C(xe2x80x94R17,xe2x80x94R18)xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94C(xe2x80x94R17,xe2x80x94R18)xe2x80x94C(xe2x95x90S)xe2x80x94, xe2x80x94Sxe2x80x94C(xe2x80x94R17,xe2x80x94R18)xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94C(xe2x80x94R17,xe2x80x94R18)xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94C(xe2x80x94R17,xe2x80x94R18)xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Sxe2x80x94C(xe2x80x94R17,xe2x80x94R18)xe2x80x94C(xe2x95x90S)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94C(xe2x80x94R17,xe2x80x94R18)xe2x80x94C(xe2x95x90S)xe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94C(xe2x80x94R17,xe2x80x94R18)xe2x80x94C(xe2x95x90S)xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94N(R16)xe2x80x94C(xe2x80x94R17,xe2x80x94R18)xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94N(R16)xe2x80x94C(xe2x80x94R17,xe2x80x94R18)xe2x80x94C(xe2x95x90S)xe2x80x94, xe2x80x94C(xe2x95x90S)xe2x80x94C(xe2x95x90S)xe2x80x94, xe2x80x94C(xe2x95x90S)xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94C(xe2x95x90S)xe2x80x94, xe2x80x94Nxe2x95x90C(xe2x80x94R17)xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Nxe2x95x90C(xe2x80x94R17)xe2x80x94C(xe2x95x90S)xe2x80x94, xe2x80x94C(xe2x80x94R17)xe2x95x90Nxe2x80x94, xe2x80x94N(xe2x80x94R16)xe2x80x94C(xe2x95x90O)xe2x80x94C(xe2x80x94R18,xe2x80x94R18a)xe2x80x94C(xe2x80x94R17,xe2x80x94R17a)xe2x80x94, xe2x80x94Oxe2x80x94C(xe2x80x94R18,xe2x80x94R18a)xe2x80x94C(xe2x80x94R17,xe2x80x94R17a)xe2x80x94, xe2x80x94N(xe2x80x94R16)xe2x80x94C(xe2x95x90S)xe2x80x94C(xe2x80x94R18,xe2x80x94R18a)xe2x80x94C(xe2x80x94R17,xe2x80x94R17a)xe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94C(xe2x80x94R18,xe2x80x94R18a)xe2x80x94C(xe2x80x94R17,xe2x80x94R17a)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94C(xe2x80x94R18,xe2x80x94R18a)xe2x80x94C(xe2x80x94R17,xe2x80x94R17a)xe2x80x94, xe2x80x94C(xe2x95x90C(R17b,xe2x80x94R17c))xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90C(R17b,xe2x80x94R17c))xe2x80x94C(xe2x95x90S)xe2x80x94, xe2x80x94N(xe2x80x94R16)xe2x80x94C(xe2x80x94R18,xe2x80x94R18a)xe2x80x94C(xe2x80x94R17,xe2x80x94R17a)xe2x80x94C(xe2x95x90S)xe2x80x94, xe2x80x94N(xe2x80x94R16)xe2x80x94C(xe2x80x94R18,xe2x80x94R18a)xe2x80x94C(xe2x80x94(N(xe2x80x94H,xe2x80x94R18b)),xe2x80x94R17a)xe2x80x94C(xe2x95x90O)xe2x80x94; xe2x80x94Nxe2x95x90C(xe2x80x94R17)xe2x80x94 and xe2x80x94N(xe2x80x94R16)xe2x80x94C(xe2x80x94R18,xe2x80x94R18a)xe2x80x94C(xe2x80x94(N(xe2x80x94H,xe2x80x94R18b)), xe2x80x94R17a)xe2x80x94C(xe2x95x90S)xe2x80x94; wherein the first named atom of the chain is directly attached to D, and wherein D, M and the N atom attached to the last chain atom of M collectively form a bicyclic ring structure;
R16, R17, R17a, R18, R18a, R18b, R19, and R19a are each independently selected from the consisting of:
hydrogen, halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, xe2x80x94CN, xe2x80x94NO2, (CH2)mNR2R3, SO2NR2R3, SO2R2, CF3, OR2, and a 5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogen atoms on the aromatic heterocyclic system may be independently replaced with a member selected from the group consisting of halo, C1-C4-alkyl, xe2x80x94CN, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl and xe2x80x94NO2;
R17b and R17c are each independently a member selected from the group consisting of
hydrogen, -halo, hydroxy, xe2x80x94C1-4alkyl, C2-6alkenyl, xe2x80x94C2-6alkynyl, xe2x80x94C3-8cycloalkyl, xe2x80x94C0-4alkyl-C3-8cycloalkyl, xe2x80x94CN, xe2x80x94NO2, xe2x80x94(CH2)mNR2R3, xe2x80x94SO2NR2R3, xe2x80x94SO2R2, xe2x80x94CF3, xe2x80x94OR2, phenyl, and a 5-6 membered aromatic heterocyclic ring containing from 1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogen atoms on the cycloalkyl, the phenyl ring, or the aromatic heterocyclic ring may be independently replaced with a member selected from the group consisting of halo, C1-C4-alkyl, xe2x80x94CN, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl and xe2x80x94NO2;
E is a member selected from the group consisting of:
a direct link, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94N(R5)xe2x80x94, xe2x80x94C(xe2x80x94R5a,xe2x80x94R6a)xe2x80x94 and xe2x80x94C(xe2x80x94R5b,xe2x80x94R6b)xe2x80x94C(xe2x80x94R5c,xe2x80x94R6c)xe2x80x94;
wherein R5, R5a, R6a, R5b, R6b, R5c and R6c are independently selected from:
H, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, C0-4alkylphenyl, C0-4alkylnaphthyl, C0-4alkylheteroaryl, C1-4alkylCOOH and C1-4alkylCOOC1-4alkyl, wherein from 0-4 hydrogen atoms on the ring atoms of the phenyl, naphthyl and heteroaryl moieties may be independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, xe2x80x94OH, xe2x80x94Oxe2x80x94C1-4alkyl, xe2x80x94SH, xe2x80x94Sxe2x80x94C1-4alkyl, xe2x80x94CN and xe2x80x94NO2;
G is selected from:
a direct link, xe2x80x94C(R7,R8)xe2x80x94, xe2x80x94C(R7a,R8a)xe2x80x94C(R7b,R8b)xe2x80x94 and xe2x80x94C(R7c)xe2x95x90C(R8c)xe2x80x94;
wherein R7, R8, R7a, R8a, R7b, R8b, R7c and R8c are independently a member selected from from the group consisting of:
hydrogen, halogen, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkyl-C3-8cycloalkyl, C0-4alkylphenyl, C0-4alkylnaphthyl, xe2x80x94OR9, xe2x80x94N(R9R10), xe2x80x94C0-4alkylCOOR9, xe2x80x94C0-4alkylC(xe2x95x90O)NR9R10, xe2x80x94C0-4alkyIC(xe2x95x90O)OR9, xe2x80x94C0-4alkylC(xe2x95x90O)NR9xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94R10, xe2x80x94C0-4alkylC(xe2x95x90O)NR9(xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94R10xe2x80x94)2, xe2x80x94N(R9)COR10, xe2x80x94N(R9)C(xe2x95x90O)R10,xe2x80x94N(R9)SO2R10, a naturally occurring or synthetic amino acid side chain, and C0-4alkylheterocyclic ring having from 1 to 4 hetero ring atoms selected from the group consisting of N, O and S, CH2COOC1-4alkyl, CH2COOC1-4alkylphenyl and CH2COOC1-4alkylnaphthyl, wherein from 1-4 hydrogen atoms on the C0-4alkylheterocyclic ring may be independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, xe2x80x94CN and xe2x80x94NO2;
wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, xe2x80x94OR9, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkyl-C3-8cycloalkyl, xe2x80x94CN and xe2x80x94NO2;
R9 and R10 are independently selected from:
H, C1-4alkyl, C0-4alkylphenyl, C0-4alkylnaphthyl, C3-8cycloalkyl, and C1-4alkyl-Oxe2x80x94C1-4alkyl, C1-4alkyl-COOH wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C26alkynyl, C3-8cycloalkyl, C0-4alkyl-C3-8cycloalkyl, xe2x80x94CN and xe2x80x94NO2, and wherein R9 and R10 taken together can form a 5-8 membered heterocylic ring;
J is a member selected from the group consisting of:
a direct link, xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94C(xe2x80x94R11, xe2x80x94R11a)xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94,xe2x80x94S(xe2x95x90O) 2xe2x80x94, xe2x80x94Sxe2x80x94C(xe2x80x94R11, xe2x80x94R11a)xe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94C(xe2x80x94R11, xe2x80x94R11a)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94(xe2x80x94R11, xe2x80x94R11a)xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94N(R11b)xe2x80x94, xe2x80x94N(R11b)xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94N(R11b)xe2x80x94, xe2x80x94N(R11b)xe2x80x94C(xe2x80x94R11, xe2x80x94R11a)xe2x80x94 and a monocyclic aromatic or non-aromatic heterocyclic ring having from 5 to 8 ring atoms, wherein 1-4 ring atoms of the ring system are selected from N, O and S, and wherein the ring system may be substituted with 0-2 R11 substituents;
R11, R11a, R11b, and R11 are a member independently selected from the group consisting of:
hydrogen, halo, xe2x80x94CF3, xe2x80x94CN, xe2x80x94NR9R10, xe2x80x94SO2Me, xe2x80x94NO2, xe2x80x94OH, xe2x80x94Oxe2x80x94C1-4alkyl, xe2x80x94Oxe2x80x94C2-6alkenyl, xe2x80x94Oxe2x80x94C2-6alkynyl, xe2x80x94Oxe2x80x94C3-8cycloalkyl, xe2x80x94Oxe2x80x94C1-4alkyl-Oxe2x80x94C1-4alkyl, xe2x80x94Oxe2x80x94C1-4alkyl-COOH, xe2x80x94Oxe2x80x94C1-4alkyl-phenyl, xe2x80x94COOH, xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94C1-4alkyl, xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94C2-6alkenyl, xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94C2-6alkynyl, xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94C3-8cycloalkyl, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkyl-C3-8cycloalkyl, C0-4alkylphenyl, C0-4alkylnaphthyl, C0-4alkylC(xe2x95x90O)NR9R10, C0-4alkylC(xe2x95x90O)OR9, C0-4alkylheterocyclic ring having from 1 to 4 hetero ring atoms selected from the group consisting of N, O and S, CH2COOC1-4alkyl, CH2COOC1-4alkylphenyl and CH2COOC1-4alkylnaphthyl; wherein from 1-4 hydrogen atoms on the C0-4alkylheterocyclic ring may be independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkyl-phenyl, C0-4alkylC3-8cycloalkyl, xe2x80x94CN and xe2x80x94NO2;
wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, xe2x80x94OR9, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkyl-C3-8cycloalkyl, xe2x80x94CN and xe2x80x94NO2;
Y is a member selected from the group consisting of:
(a) phenyl, which is independently substituted with 0-2 R1b substituents;
(b) naphthyl, which is independently substituted with 0-2 R1b substituents; and
(c) a monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are selected from N, O and S, and wherein the ring system may be substituted with 0-2 R1b substituents;
R1b is a member selected from the group consisting of:
halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloaklyl, C0-4alkylC3-8cycloalkyl, xe2x80x94CN, xe2x80x94NO2, NR2bR3b, SO2NR2bR3b, SO2R2b, CF3, OR2b, Oxe2x80x94CH2xe2x80x94CH2xe2x80x94OR2b, Oxe2x80x94CH2-COOR2b, N(2b)xe2x80x94CH2xe2x80x94CH2xe2x80x94OR2b, N(xe2x80x94CH2xe2x80x94CH2xe2x80x94OR2b)2, N(R2b)xe2x80x94C(xe2x95x90O)R3b, N(R2b)xe2x80x94SO2xe2x80x94R3b, and a 5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogen atoms on the aromatic heterocyclic system may be independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, C0-4alkyl-phenyl, xe2x80x94CN and xe2x80x94NO2;
R2b and R3b are independently selected from the group consisting of:
H, C4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloaklyl, C0-4alkylC3-8cycloalkyl, C0-4alkylphenyl and C0-4alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, xe2x80x94OR9, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycoalkyl, xe2x80x94CN and xe2x80x94NO2;
L is selected from:
H, xe2x80x94CN, C(xe2x95x90O)NR12R13, xe2x80x94(CH2)nNR12R13, C(xe2x95x90NR12)NR12R13, OR12, xe2x80x94NR12C(xe2x95x90NR12)NR12R13, and NR12C(xe2x95x90NR12)xe2x80x94R13;
n is an integer from 0 to 8;
R12 and R13 are independently selected from:
hydrogen, xe2x80x94OR14, xe2x80x94NR14R15, C1-4alkyl, C0-4alkylphenyl, C0-4alkylnaphthyl, COOC1-4alkyl, COOxe2x80x94C0-4alkylphenyl and COOxe2x80x94C0-4alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, xe2x80x94OH, xe2x80x94Oxe2x80x94C1-4alkyl, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, xe2x80x94CN, and xe2x80x94NO2;
R14 and R15 are independently selected from:
H, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, C0-4alkylphenyl and C0-4alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C1-4alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C0-4alkylC3-8cycloalkyl, xe2x80x94CN, and xe2x80x94NO2;
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof.
In certain aspects of this invention, compounds are provided which are useful as diagnostic reagents. In another aspect, the present invention includes pharmaceutical compositions comprising a pharmaceutically effective amount of the compounds of this invention and a pharmaceutically acceptable carrier. In yet another aspect, the present invention includes methods comprising using the above compounds and pharmaceutical compositions for preventing or treating disease states characterized by disorders of the blood coagulation process in mammals, or for preventing coagulation in stored blood products and samples. Optionally, the methods of this invention comprise administering the pharmaceutical composition in combination with an additional therapeutic agent such as an antithrombotic and/or a thrombolytic agent and/or an anticoagulant.
The preferred compounds also include their pharmaceutically acceptable isomers, hydrates, solvates, salts and prodrug derivatives.